A relatively rare traditional Chinese medicine pattern of primary Sjögren syndrome: A case report

Rationale: This report presents a unique case of a patient diagnosed with Primary Sjögren’s syndrome and a relatively rare traditional Chinese medicine pattern, known as the combined cold and heat pattern and cold-dampness syndrome. The patient’s condition was successfully managed using Chinese herbal medicine, specifically the modified Da-Chai-Hu decoction and Linggui Zhugan decoction. Patient concerns: A 56-year-old woman had chronic dry eye and mouth for over 10 years. She was initially managed with traditional Chinese herbal medicine (TCHM) prescriptions, including the Zengye decoction, but the therapeutic effects were unsatisfactory. As the disease progressed, she was diagnosed with an anxiety disorder due to symptoms of vexation and insomnia. Treatment with alprazolam and venlafaxine failed to alleviate these symptoms. Recently, her general condition gradually worsened, with symptoms including a bitter taste in her mouth, dizziness, hot flashes, chills, poor appetite, chest discomfort, and constipation. Diagnoses: After a series of examinations, including a Schirmer test and labial gland biopsy, she was diagnosed with Sjögren’s syndrome. Interventions: Despite regular treatment with pilocarpine, sodium hyaluronate eye drops, venlafaxine, and alprazolam, the dry mouth symptoms intensified. Consequently, she sought further intervention through the TCHM. Outcomes: After 8 weeks of treatment with the modified Da-Chai-Hu decoction and Linggui Zhugan decoction, she reported a significant improvement in her dryness-related symptoms and sleep quality. Lessons: This case report demonstrates that TCHM can effectively treat Primary Sjögren’s syndrome, and should be considered for broader applications. Furthermore, this underscores the importance of tailoring treatment formulas to patients by identifying their specific syndrome differentiation in a clinical setting.


Introduction
Sjögren syndrome (SS) is a common chronic autoimmune disease that affects multiple organs and tissues. [1]In most cases, clinical manifestations are characterized by persistent xerostomia and xerophthalmia, resulting from immune-mediated impairment of the salivary and lacrimal glands.Lymphocytic infiltration also occurs in the epithelial tissues of organs beyond the exocrine glands, leading to systemic symptoms, such as nephritis, bronchiolitis, muscle weakness, and pain. [2,3]otably, SS is reported to be present alone or in combination with other systemic autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis; thus, SS can be classified into primary SS (pSS) and secondary SS. [4]Epidemiological data indicate that the prevalence rate of pSS is 0.03% to 5% worldwide, with a 1:9 maleto-female ratio, and that pSS occurs primarily at ages between 20 to 30 and 50 to 70 years. [5,6]So far, although the etiology of pSS is largely unclear, genetic variants, environmental factors, infection, and family history may be implicated in the pathogenesis. [5,7]urrently, the available treatment options are limited, mainly focusing on relieving symptoms, improving quality of life, and managing complications.Artificial tears and saliva secretion stimulators are the first-line treatments in clinical practice. [8]atients with systemic complications require immunosuppressants and/or steroid therapy to improve symptoms and reduce complications such as nephritis and joint symptoms. [9]These drugs, however, have not been proven to be highly efficacious in the treatment of pSS. [10]Additionally, the accompanying side effects of these drugs are difficult to ignore.Doctors would make a more targeted treatment decision in the clinical setting based on their own experience. [10]raditional Chinese herbal medicine (TCHM) is widely used to treat pSS in China. [11,12]According to traditional Chinese medicine (TCM) principles, pSS belongs to the category of ''dryness-bi" and most patients with pSS have hyperactivity of fire due to Yin deficiency, blood stasis, and phlegm stagnation. [13]he treatments are to nourish yin, clear heat, remove blood stasis, and resolve phlegm.Various TCHMs have been reported for the treatment of pSS.This case report details the experience of a patient with pSS who exhibited a relatively rare combined cold and heat pattern, as well as cold-dampness syndrome.Despite persistent symptoms of dry mouth, dry eyes, chills, and constipation, and a poor response to first-line conventional drugs and Yin-nourishing treatment, the patient was successfully treated with a regimen involving the modified Da-Chai-Hu decoction (DCHD) and Linggui Zhugan decoction (LGZGD).However, this TCM pattern and treatment approach have not been previously reported.The aim of presenting and discussing this case is to share our insights with clinicians and offer an alternative treatment option for patients with similar conditions.

Case presentation
Herein, we describe the case of a 56-year-old female who visited our hospital in September 2021 with symptoms of dry eye and dry mouth for the past 10 years.The patient had visited several hospitals for treatment.However, no definite diagnosis could be made because of negative antinuclear antibody and rheumatoid factor test results.Oral TCHM prescriptions have been attempted, including the Zengye decoction (ZYD), which consists of Radix scrophulariae, Ophiopogon japonicus, and Radix rehmannia; however, the effects were not good.She denied a history of diabetes mellitus or insipidus.In addition, owing to the presence of vexation and insomnia, she was diagnosed with anxiety disorder by a physician from the mental health department and treated with venlafaxine and alprazolam for some time.She stopped taking this medication independently due to failed symptomatic relief.Over the past 4 months, the symptoms of dry mouth gradually worsened.Sleep was severely impaired, especially at night, accompanied by a bitter taste in the mouth, dizziness, hot flashes, chills, poor appetite, chest discomfort, and constipation.Therefore, the patient sought treatment again at the hospital.
Physical examination showed that the patient had a stringy pulse, tender, and reddish tongue, and yellow greasy fur without rampant caries, joint swelling, and tenderness (Fig. 1A).Routine laboratory tests were performed and the results showed no apparent abnormalities, including blood routine, biochemistry, blood sugar, C-reactive protein, erythrocyte sedimentation rate, immunoglobulin G, immunoglobulin A, immunoglobulin M, rheumatoid factor, complement levels (C3 and C4), and tumor-associated markers.Notably, dry eye disease was evidenced by a positive Schirmer test result (left eye, 2 mm/5 min; right eye, 2 mm/5 min), which is a routine method for evaluating lacrimal gland function.Minor salivary gland biopsy revealed increased focal lymphocytic infiltration (>1 focus per 4 mm 2 and approximately 200 lymphocytes per high power field) (Fig. 2).Magnetic resonance imaging of the head revealed normal findings.The throat mucosa showed obvious congestion on laryngoscopy, and laryngopharyngeal reflux and pharyngitis were suspected.According to the 2016 ACR/EULAR classification criteria for SS, [14] the patient fulfilled the inclusion criteria with a weighted summed score of 4 points and was diagnosed with pSS.
First-line conventional treatments for pSS, including pilocarpine, sodium hyaluronate eye drops, and anxiolytics (venlafaxine and alprazolam), were prescribed to alleviate dryness and anxiety.However, this approach yielded no clinical benefits, and the patient's dry mouth progressively worsened.Consequently, the patient sought help from the TCHM.According to the TCM theory, the patient exhibited a dryness bi syndrome mixed with a cold-heat complex and cold-dampness blockage.Based on the TCM syndrome type and physical findings, the patient was administered the modified DCHD and LGZGD (Table 1), and 1 pack of decoction (200 mL) was consumed twice daily.These treatments are known for their effects of warming Yang, invigorating the spleen, eliminating dampness, and relieving the exterior-interior syndrome.After 5 days of treatment, the patient's dry mouth symptoms were noticeably relieved, and her tongue manifestations improved (Fig. 1B).After 8 weeks of treatment, the patient reported a significant improvement in her symptoms, with only slight dry mouth and chills remaining.The tongue coating returned to a nearly normal state (Fig. 1C).The timeline of disease progression and treatment is shown in Figure 3.

Discussion
This report presents a case in which pSS was effectively managed with TCHM.The patient's pSS-related symptoms were largely alleviated, and some clinical signs returned to normal.The use of the modified DCHD and LGZGD in treating pSS has not been previously reported.In this case, the efficacy of these decoctions in clinical practice was confirmed, providing further evidence of the unique advantages of the dialectical treatment system in TCM for managing complex diseases.
SS is a chronic progressive autoimmune disorder characterized by inflammatory infiltration of the exocrine glands, resulting in secretory dysfunction and serious complications including depression, fatigue, and systemic autoimmunity. [3,15]ndeed, many inflammatory mediators and cells play a critical and complicated role in the pathogenesis of pSS, such as B cell-activating factor, a proliferation-inducing ligand, interleukin 12, interferon-γ, plasmacytoid dendritic cells, T cells, and B cells. [10]For patients, once a clinical diagnosis is firmly established, the currently available treatment options for pSS, such as muscarinic agonists and immunomodulatory drugs, can only relieve symptoms and prevent acute exacerbation.However, it is not uncommon for these interventions to not achieve a satisfactory improvement in some cases, and these medications often inevitably cause serious side effects. [3]onsequently, the search for more potent alternative drugs or combined strategies against pSS is necessary.Recently, many studies have shown that TCM can effectively improve the major symptoms of pSS and delay its progression by upregulating aquaporin proteins, inhibiting cell apoptosis, and preventing abnormal T and B cells activation. [13]It suggests that TCM is a treasure trove for discovering novel drugs against pSS.
From the perspective of TCM, Yin deficiency syndrome is one of the most common syndromes in pSS patients.ZYD is a well-known TCM prescription for nourishing Yin in China, which can promote an increase in body fluids.However, in this case, the patient did not respond to ZYD because of a complex condition.The patient's symptom-alternating fever and chills are manifestations of the struggle between antipathogenic qi and pathogenic factors outside and the inside.Moreover, vexation, bitter taste, and appetite are manifestations of heat in the gallbladder and stomach; heat and fluid deficiency correspond to dry throat; gallbladder heat corresponds to dizziness and dry eye; fullness in the chest and subcostal region points to Shaoyang disease; stasis due to exterior evil inward invade and transform to heat causes hot flashes and constipation, the symptom of Yangming disorder.The patient was diagnosed with Yangming and Shaoyang Syndrome Complex.Reddish tender tongue, thick greasy coating, and stringy pulse are signs of cold-dampness impediment.Thus, the patient had a cold-heat complex and cold-dampness impediment pattern.Meanwhile, the modified DCHD and LGZGD were used to release both exterior and interior, warm Yang, and transform dampness.
DCHD, a famous formula recorded in the "Treatise on Febrile Diseases," is a classic formula for Yangming and Shaoyang Syndrome Complex through harmonizing and releasing Shaoyang and clearing interior excess heat.Previous studies have reported the efficacy of DCHD in the clinical treatment of various diseases, such as acute intrahepatic cholestasis, [16] acute liver injury, [17] cardiovascular disease, [18] nonalcoholic fatty liver disease, [19] pancreatic fibrosis, [20] diabetes, [21] gastrointestinal disease, [22] mental illness [23] by inhibiting inflammation, reducing oxidative stress, and improving lipid and glucose metabolism.Additionally, Zhongjing Zhang described LGZGD in the "Synopsis of Prescriptions of the Golden Chamber" (also named "Jingui Yaolüe").It is widely used to warm the yang and fortify the spleen to move water.With the recent development of mass spectrometry and multiomics analysis techniques, modern pharmacological research has gradually uncovered the underlying molecular mechanisms by which TCM formulas with complex components in the treatment of various diseases.Multiple natural herbs from these formulas have anti-inflammatory, antioxidant, immune regulation, anticancer, antiaging, anxiolytic, and analgesic properties, including Radix Bupleuri, Radix Paeoniae Alba, Rhubarb, Atractylodes macrocephala, and Poria cocos, [24][25][26][27][28][29] which may be the possible molecular mechanism in treating pSS.
It is worth noting that the patient had not yet suffered systemic organ damage despite suffering from the disease for nearly 10 years.Consequently, the patient had good prognosis in response to reasonable TCM prescription treatment.Further studies are required to determine whether similar therapeutic effects can be observed in the general population.

Conclusion
The modified DCHD and LGZGD show promise as standalone treatments for patients with pSS who exhibit a combined cold and heat pattern and cold-dampness syndrome.These herbal formulations could be viable treatment alternatives for patients with similar clinical conditions.Table 1 The component of the modified Da-Chai-Hu decoction and Linggui Zhugan decoction.

Botanical name
Chinese name Dosages (g/100 mL)